Melanoma represents only up to 5% of all skin cancers 1, but is clearly clinically the most aggressive type of skin cancer.
In Denmark, 1800 new cases of melanoma were diagnosed in 2010, making it the fifth most common cancer in Denmark. In comparison, only 700 patients with melanoma were diagnosed in Denmark in 1997. During the investigation period, ∼100 patients/year were diagnosed with metastatic melanoma not amenable to surgery. Approximately 20% of these patients had rapidly progressive disease and poor performance status and were not candidates for interleukin-2 (IL-2)-based immunotherapy 2.
IL-2-based immunotherapy has formed the basis for the treatment of metastatic melanoma in Denmark since 1995 and, in 2008, high-dose intravenous IL-2 was granted status as the standard of care in patients considered eligible for this type of intensive immunotherapy 2. Patients were evaluated before treatment with clinical examination, and contrast-enhanced computed tomography (CT) scans of the brain, chest, abdomen, and pelvic region.
Melanoma is responsible for 10% of all cases of brain metastases and ranks third highest in the incidence of brain metastases in solid tumors 3. Central nervous system (CNS) involvement leads to early death in the majority of cases, with a median survival between 2 and 4 months 4–6, in selected cases reaching up to 9 months 7. Published data have proven the high propensity to metastasize to the brain, indicating that up to 40% of melanoma patients will develop brain metastases during their clinical course. However, even higher incidence of brain metastases has been observed in autopsies, where up to 75% of patients have brain metastases, suggesting that many patients have asymptomatic disease 8. For this reason, since 2009, the American Joint Committee on Cancer has recommended staging with contrast-enhanced MRI of the brain in patients with known metastatic skin melanoma 9.
In this retrospective study, we aimed to examine the frequency of asymptomatic brain metastases, detected by contrast-enhanced CT scans in the patient population admitted for IL-2-based treatment for metastatic skin melanoma.
Patients and methods
Between 1995 and 2009, 763 patients with biopsy-verified metastatic skin melanoma were referred to the Departments of Oncology at Odense and Aarhus University Hospitals. During this period, these two departments were responsible for first-line therapy of all Danish patients with metastatic melanoma. Only patients with metastatic skin melanoma referred to first-line IL-2-based immunotherapy were included in the present analysis. After strict evaluation of clinical and radiographic cases, 66 patients with poor clinical conditions, significant comorbidity, or symptomatic brain metastases were offered palliative treatment (palliative radiation, palliative surgery, corticosteroids, or hospice). Therefore, the final analyses included 697 patients screened before the start of IL-2-based immunotherapy. Since 2007, the standard regimen has been high-dose intravenous IL-2 and interferon in a modified decrescendo regimen 10, which was approved by our ethical committee as well as other IL-2-based protocols at the time. All patients were screened with CT scans of the brain, chest, abdomen, and pelvic region, and supplemented with an MRI scan of the brain in patients where the CT scan was not conclusive. Both CT and MRI were contrast enhanced.
Between 1995 and 2008, a standard CT-brain in our department was 5 mm sequential (not spiral) sections in the basal ganglia, tilted along the skull base, and 10 mm sections in the brain above the basal ganglia. After 2008, the standard CT-brain 5 mm sequential (not spiral) section through the whole brain tilted along the skull base. During the period investigated, MRI was not a standard imaging method for screening of patients without clinical symptoms, suggesting the presence of brain metastases. Whole-body CT with 100 ml of intravenous contrast was used to evaluate the distribution of metastatic melanoma.
Data were recorded and analyzed in a Medlog database (v.2008-2 for Windows; Information Analysis Corporation, Crystal Bay, Nevada, USA). Statistical analyses for baseline demographics were descriptive. The median overall survival was estimated using the Kaplan–Meier method and survival data were compared using the log-rank test. Overall survival was calculated as the period from the diagnosis of metastatic melanoma until death or the latest follow-up performed on 1 March 2011.
The group of patients with asymptomatic brain metastases was comparable with the group without brain metastases with respect to sex, age, primary melanoma site, and histology. However, the frequency of visceral metastases was significantly higher in the group of patients with asymptomatic brain metastases (Table 1).
Multidisciplinary conferences involving radiologists and oncologists formed the basis of the decision-making on the disease stage. In our cohort of 697 patients, we detected 80 (12%) patients with asymptomatic brain metastases by CT scans with contrast. In 32 (40%) of the 80 patients with solitary lesions on contrast-enhanced CT scans, which were not defined as metastatic, confirmatory MRI of the brain with contrast was carried out. In the 80 patients with asymptomatic brain metastases, 25 (31%) had a single metastatic lesion, 19 patients (24%) had two or three lesions, and 36 patients (45%) had more than three lesions. The detection rate of asymptomatic brain metastases was increasing in 5-year periods: 4.4% before 2000, 10.4% between 2000 and 2005, and 13.7% after 2005 (P=0.008). Histological confirmation of metastatic melanoma in the brain was obtained in four patients. In all other cases, biopsy verification of metastatic melanoma was achieved using more accessible metastatic lesions outside the brain.
Of all 697 patients, 72 did not receive any kind of treatment, 33 were among patients with asymptomatic brain metastases, and 40 were in the group of patients without brain metastases.
The treatment for patients with and without asymptomatic brain metastases is presented in Table 2. The main reasons for not receiving IL-2-based treatment were poor and rapidly declining performance status during the screening period, waiting for treatment to begin, or patients’ refusal to receive immunotherapy. Other systemic treatment for patients without brain metastases was ipilimumab (nine patients), T-cell therapy (11 patients), AZD6244 (one patient), dendritic cell vaccine (one patient), and temozolomide and thalidomide (11 patients) 11,12. Palliative treatment was either surgery (five patients) or radiotherapy (eight patients), mostly as palliation for other cutaneous or distant metastases than those in the brain.
In the group with asymptomatic brain metastases, 47 of 80 patients received systemic treatment with (n=11) or without (n=36) local treatment of brain metastases. Seventeen patients received IL-2-based therapy, one patient received T-cell therapy, and 29 patients received treatment with temozolomide. In the 17 patients receiving IL-2-based therapy, seven patients were treated after surgery, stereotactic radiotherapy, or whole-brain radiotherapy (WBRT). A total of 20 patients received only local treatment for brain metastases in the form of WBRT (n=18), stereotactic radiotherapy (n=1), or surgery plus WBRT (n=1). Among patients receiving IL-2-based treatment, nine had a single asymptomatic brain metastasis, four had two to three metastases, and four had more than three metastases.
In univariate analysis, survival was significantly shorter in patients with asymptomatic brain metastases, compared with patients without brain metastases. The median survival was 4.5 months in patients with asymptomatic brain metastases, compared with 9.2 months in the group without brain metastases (HR 1.7, 95% confidence interval: 1.3–2.1; P<0.0001) (Fig. 1). The 1-year survival was 12.5 and 38.4% in the two groups with or without asymptomatic brain metastases, respectively.
The incidence of asymptomatic brain metastases associated with metastatic skin melanoma and confirmed by imaging has not been studied previously. Sampson et al.8 have previously described clinically significant brain metastases in 702 melanoma patients, supporting the dismal prognosis of these patients. However, they also identified a subgroup with surgically amenable single brain metastases, without concomitant extracranial metastatic disease surviving for 3 or more years.
Korn et al.13 analyzed published phase II trials with metastatic melanoma, and in the papers, which also included patients with brain metastases, they found a median overall survival of 5.2 months, with 20% 1-year overall survival. Retrospective analyses of patients with brain metastases also show a median survival not exceeding 5.8 months. However, in a selected group with brain metastases, where surgical resection is possible, the median overall survival reaches up to 9 months 3,7,14–17. Recently published data 15,16 show increasing survival of patients with brain metastases over the past decades, possibly as a reflection of the introduction of more sensitive imaging techniques such as MRI, and advances in the subsequent treatment after careful patient selection.
The routine use of CT scans of the brain for staging of skin melanoma before systemic treatment makes it possible to estimate the incidence of asymptomatic brain metastases with a detectable size. Contrast-enhanced CT scans and MRI are standard techniques for imaging the brain. However, comparison of the accuracy of whole-body MRI and CT shows the superiority of MRI. MRI can detect more metastases (40% more) than CT alone 18. MRI-detected CT-negative brain metastases represent a group of patients with low-volume disease. This group can be treated safely with IL-2-based therapy 19. The routine use of 18F-fluorodeoxyglucose positron emission tomography for staging of melanoma is increasing, although the resolution for brain metastases makes this modality insufficient for use as an imaging procedure for the detection of brain metastases. Pfanneberg et al.20 have shown that in 64% of patients with metastatic skin melanoma, whole-body PET/CT influenced a choice of treatment. On comparing CT with MRI and PET/CT with MRI, the studies confirmed the detection of CNS involvement as being most accurate using MRI. In our cohort, all patients underwent screening with CT of the brain. This was primarily done because treatment with high-dose IL-2 is known to increase tumor size intermittently because of an immune-related reaction. This may be problematic in patients with large-volume brain metastases. The increasing detection rate of our cohort may be associated with the changing referral pattern of patients with cutaneous melanoma by referring physicians. There was no indication of significant changes in the quality of CT scans that could explain this increase in the detection rate over time. Our screening method for brain metastases using CT scans alone has probably led to an underestimation of the number of asymptomatic brain metastases. This is fully justified as the aim was to detect large-volume metastases, potentially causing harm in connection with IL-2 treatment. However, if the goal is to detect the presence of brain metastases, for instance during the evaluation of new treatment strategies, it is necessary to use MRI with contrast, as recommended by the NCCN (http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf).
The major reason why patients with melanoma have had such a dismal prognosis has been the lack of effective systemic treatment modalities. For patients with brain metastases, many retrospective analyses have confirmed that selected patients with few brain metastases have a better prognosis using local treatment interventions. Treatment strategies for selected melanoma patients with good performance status and with limited number of brain metastases include surgical resection or stereotactic radio surgery 21,22 as well as a combination of local therapy and immunotherapy 1. Various treatment combinations have also been used in the treatment of our patients with asymptomatic brain metastases, with the longest survival in a group that was suitable for local treatment combined with immunotherapy. These patients, however, were selected because of their limited brain involvement, and no firm conclusion on treatment efficacy can be extracted.
Management of brain metastases has been difficult because of general resistance to cytotoxic chemotherapy in metastatic melanoma. Temozolomide has been evaluated in the treatment of brain metastases 23. The study showed a 6% overall response rate in brain metastases, with a slightly better clinical response in patients who had not received previous chemotherapy for brain metastases. The results are fully comparable with the response rates in extracranial metastatic lesions in patients treated with temozolomide, indicating that the macroscopic brain metastases may be treated with systemic treatment modalities 24.
Nonspecific stimulation of the immune system using cytokines such as IL-2 and interferon has been used for almost three decades either as single drugs or in combination with other immune-enhancing therapies, yielding response rates up to 27% 25. Traditionally, the brain has been considered a sanctuary for immunotherapy, and furthermore, the risk of CNS toxicity because of tumor edema has made brain metastases a relative contraindication for IL-2-based therapy. However, retrospective reviews with high-dose IL-2 treatment 19–26 or IL-2 in combination with chemotherapy 4 in highly selected patients with brain metastases provide indications that CNS involvement should not be an absolute exclusion criterion for IL-2-based immunotherapy 27. In a review by Guirguis et al.19, a response rate of 18% was observed using high-dose IL-2 in pretreated patients with brain metastases, and an overall response rate of 6% was obtained in previously untreated patients with brain metastases from melanoma or renal cell carcinoma.
Recently, new treatment strategies such as blockade of negative regulators of the immune response (anti-CTLA4) and inhibitors of the mutated BRAF kinase have yielded positive results in reducing the risk of death, improving the response durations and survival rates, not seen before in the treatment of metastatic melanoma 28–30. Safety and survival analyses, using ipilimumab in patients with asymptomatic and symptomatic brain metastases, have yielded acceptable toxicity and efficacy, with a 1-year overall survival rate of 31% in patients with stable brain metastases 31,32. The latest phase II trial conducted by Margolin and colleagues established that ipilimumab is active in selected patients with stable, asymptomatic melanoma brain metastases who do not need treatment with systemic corticosteroids. The patients with asymptomatic brain metastases achieved 18% disease control after 12 weeks, with a median overall survival of 7 months and 55, 31, 26, and 26% overall survival at 6, 12, 18, and 24 months, respectively 33. The other large change in the treatment strategy of metastatic melanoma is related to agents targeting specific mutations identified in melanoma cells. Up to 50% of cutaneous melanomas harbor an activating mutation in the BRAF kinase, leading to the activation of parts of the MAPK pathway, which regulates cell proliferation 34. Treatment with vemurafenib in patients with the BRAF V600E mutation has yielded a response rate of 48% and improved overall and progression-free survival times compared with treatment with dacarbazine 30. Early results for BRAF inhibitors in patients with brain metastases have emerged. An open-label single-arm trial is ongoing, where vemurafenib is being administered to patients with brain metastases. Results from four patients show that the treatment is being well tolerated and the staging report of two patients indicated one partial response and one minor response in the brain 35. The BRAF inhibitor dabrafenib (GSK2118436) has shown an effect on patients with asymptomatic brain metastases and a phase I dose-escalation trial has been published recently by Falchook et al. 36. In a limited number of patients with untreated brain metastases, with both Val600Glu BRAF mutations (n=9) and non-Val600Glu BRAF mutations (n=1), nine of 10 patients achieved reductions in the size of brain lesions and four of 10 patients achieved a complete response, with all 10 patients alive at 5 months. Furthermore, both phases II and III trials with dabrafenib are underway 37. ASCO 2012 included a report on dabrafenib in patients with brain metastases with BRAF V600E/K 37. The overall intracranial response rate in patients without pretreated brain metastases and in patients with treated brain metastases for V600E was 53%, and for patients with V600K, it was 20%. Up to an 80% overall disease control rate may be achieved in this highly selected patient group.
We have found a 12% incidence of asymptomatic brain metastases, using contrast-enhanced CT of brain in selected patients with metastatic cutaneous melanoma referred for IL-2-based immunotherapy. Proper staging procedures for brain metastases in metastatic melanoma patients before systemic treatment should include contrast-enhanced MRI of the brain, in light of the potential efficacy of new antineoplastic treatment modalities and the inclusion of patients with brain metastases in clinical trials.
Conflicts of interest
There are no conflicts of interest.
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